GENE-01. TUMOR MUTATION BURDEN AND DRIVER MUTATIONS: FURTHER INSIGHT INTO THE GENOMIC LANDSCAPE OF PEDIATRIC HIGH GRADE GLIOMAS

Pediatric high grade gliomas (HGG) have been described to have a higher tumor mutation burden (TMB) than low grade gliomas. A high TMB has been associated with improved objective immune checkpoint inhibitor (ICPI) response and progression-free survival in adult HGG. There is also data to suggest that tumors with a high TMB are less likely to possess a mutation in a cancer driver gene. To better characterize the range of TMB in pediatric HGG, and the relationship to mutations in cancer driver genes, we analyzed a cohort of HGG tumor specimens. DNA was extracted from 40 microns of formalin-fixed paraffin-embedded (FFPE) specimen from a set of 93 cases of pediatric (≤18 years) HGG. Hybridization capture of 567 cancer-related genes and select introns from genes commonly rearranged in cancer was performed on DNA extracted from 3,983 clinical FFPE specimens and sequenced to high, uniform coverage (>500x). TMB was assessed as the number of somatic coding point mutations per megabase of targeted territory. Cases were analyzed for the presence of known cancer driver gene mutations. Thirteen (14%) tumors had a TMB >10 mutations per megabase, 9 (10%) had a TMB >40, and 7 (7.5%) had a TMB >100. Eighteen (23%) of the 79 patients with a low TMB <10, 3 (23%) of the 13 patients with a TMB >10, and 1 (11%) of the 9 patients with a high TMB >40, had at least one driver mutation. Driver mutations identified included PIK3CA, BRAF, EGFR, IDH1, KRAS, HRAS. A substantial subset of pediatric HGG tumors possess a high TMB and, while it did not reach statistical significance, there was a trend toward decreased incidence of cancer driver mutations in high TMB tumors. Studies are needed to evaluate if TMB and driver mutation status in pediatric HGG is predictive of response to ICPI.